Pontocerebellar Hypoplasia via the SEPSECS Gene

Pontocerebellar hypoplasias (PCH) are a group of clinically and genetically heterogeneous neurodegenerative disorders characterized by abnormal development of the pons, cerebellum and cerebral cortex; progressive microcephaly; psychomotor developmental delay; and swallowing difficulties (Barth. 1993. PubMed ID: 8147499; Namavar et al. 2011. PubMed ID: 21368912). Several subtypes have been described based on the clinical presentation, progression, and pathological and molecular defects. However, clinical overlapping features among various subtypes have been reported, and some genes have been implicated in more than one subtype, suggesting that PCH constitute a spectrum (Burglen et al. 2012. PubMed ID: 22452838; Samanta and Willis. 2016. PubMed ID: 27570394).

PCH2D is also known as progressive cerebellocerebral atrophy (PCCA). Clinical features include developmental delay, sleep disturbance, irritability, slurred speech, spastic quadriplegia, seizures, choreiform movements, dysmetria, tonic upgaze, nystagmus, hypotonia and intellectual disability. Optic nerve atrophy and mild secondary mitochondrial myopathy have been reported in some cases (Ben-Zeev et al. 2003. PubMed ID: 12920088; Agamy et al. 2010. PubMed ID: 20920667; Iwama et al. 2016. PubMed ID: 26888482; Pavlidou et al. 2016. PubMed ID: 26805434).

All pontocerebellar hypoplasias are transmitted with an autosomal recessive mode of inheritance. PCH2D is caused by pathogenic variants in the SEPSECS gene (Anttonen et al. 2015. PubMed ID: 26115735). To date, about 10 pathogenic variants have been identified. Half of the variants are missense and the other half are of the truncating type, including one single exon deletion (Human Gene Mutation Database).

SEPSECS encodes the SepSecS protein that is involved in mammalian brain development and function (Agamy et al. 2010. PubMed ID: 20920667; Zhang and Zarbl. 2008. PubMed ID: 19122877).

Pathogenic variants in the SEPSECS gene appear to be rare. Such variants have been reported in a total of 13 unrelated patients.

Copy number variants also appear to be rare. Only one single exon deletion has been reported to date (Iwama et al. 2016. PubMed ID: 26888482; Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SEPSECS gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.